PROJECT SUMMARY Age-related cognitive decline is a significant public health concern as the population over the age of 60 continues to grow sharply. Advances in understanding the mechanisms that underlie this decline will allow for effective interventions and substantially reduce the burden on families as well as government and social programs. We will be faced with 50 trillion dollars in Medicare costs as the baby boomers age, thus magnifying the size of the concern and the significance of our proposed work. Aging is a major risk factor for Alzheimer?s disease (AD), which currently affects over five million Americans. If no prevention or treatment is discovered, this number could increase to 16 million by 2050. Establishing early indicators of the disease process during the preclinical stage is a critical goal of biomedical research. Our funded parent NIA R01AG053555 grant aims to determine the neural features (i.e. biomarkers) associated with amyloid pathology accumulation, and determine objectively how to combine these biomarkers to identify individuals with preclinical AD. The project combines amyloid imaging, state-of-the-art high-resolution multimodal MRI tools, and targeted, innovative cognitive testing approaches (hippocampal pattern separation tests). We will conduct PET amyloid scans with [18F] AV-45 (florbetapir) on all participants to determine amyloid status (targeting 50% positivity across the whole sample). We will conduct high-resolution multimodal MRI and targeted cognitive examinations in all participants at baseline, and repeat the cognitive examinations contemporaneously with ADRC annual and bi- annual follow-up visits. This proposal for a competing revision extends the scope of the parent project by adding (1) baseline and follow-up tau PET assessment via the experimental novel tau tracer [18F]MK6240 to determine tau burden, spatial distribution, and temporal progression over 12-18 months, and (2) concurrent follow-up MRI scans to track possible neurodegenerative decline in medial temporal lobe structure and function. Combining baseline and longitudinal MRI with baseline and longitudinal tau PET addresses a critical gap in available data in preclinical AD. Use of [18F]MK6240 is additionally an innovative feature as currently there are no large-scale studies using this tracer in preclinical AD and early data suggest that it does not have some of the shortcomings associated with other tracers (in particular, off-target binding). Our unique PET and MRI scanner resolutions also afford unprecedented advantages in examining spatial distributions of pathology and neurodegeneration. Collectively, the extension to the project proposed here adds tremendous value to the already funded project. The proposed work will provide a rich dataset with several unique aspects that will significantly inform our understanding of cognitive decline in the aging brain in the presence and absence of amyloid and tau pathology and allow us to better define preclinical AD and make recommendations for future intervention trials.